Glutamate receptors are the primary mediators of excitatory synaptic transmission in the central nervous system. Glutamate is one of the twenty (20) common amino acids, but it is also functions as a ligand for glutamate receptors. Glutamate is particularly abundant in the nervous system where it functions as a neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated post-synaptic excitation of neural cells, and are important for neural functions including neural communication, memory formation, learning, and physiological regulation. Accordingly, glutamate receptors have been implicated in the pathologies of a number of neurological diseases and disorders.
Glutamate receptors can be divided into two groups based on the mechanism by which their activation gives rise to a post-synaptic current. “Ionotropic” glutamate receptors (iGluRs) form an ion channel pore that is activated when glutamate binds to the receptor. “Metabotropic” glutamate receptors (mGluRs) indirectly activate ion-channels on the plasma membrane through a signaling cascade that involves G-proteins.
There are many specific subtypes of glutamate receptors, and it is customary in the field to refer to receptor subtypes by a chemical agonist which binds to the receptor more selectively than glutamate. Agonists include kainate which is a salt of kainic acid, N-methyl-D-Aspartate (NMDA), and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA).
Kainate receptors (KARs), one subgroup of the ionotropic glutamate receptor family, have roles in brain physiology and pathology that are poorly characterized. Natural source compounds have been useful tools for identification and characterization of these receptors and their role in many processes. In particular, dysiherbaine (DH) has been isolated from the Micronesian sponge Dysidea herbacea and has been found to be a potent kainate receptor agonist and subsequently, a powerful convulsant. (See Sakai et al., J. AM. CHEM. SOC. 1997; 119:4112-16; and Sakai et al., JPET 2001; 296:650-8, the contents of which are incorporate by reference in their entireties). Kainate receptor-selective epimeric analogs of dysiherbaine and the use thereof in pharmaceutical compositions and methods are disclosed in U.S. Published Application No. 2009-0118358, the content of which is incorporated by reference in its entirety.
NMDA receptors (NMDARs), another subgroup of the ionotropic glutamate receptor family, are a predominant physiological effector for synaptic plasticity and memory function. Activation of NMDARs results in the opening of an ion channel that is non-selective with respect to cations. NMDARs exhibit voltage-dependent activation as a result of Mg2+ ions binding and blocking the ion channel. This allows voltage-dependent flow of Na+ and small amounts of Ca2+ ions into the cell and flow of K+ ions out of the cell.
AMPA receptors (AMPARs), another subgroup of the ionotropic glutamate receptor family, also are responsible for excitatory neurotransmission in the mammalian central nervous system. Over-activation of AMPARs receptors contributes to the pathology of a number of neurological diseases, particularly epilepsy, neuropathic pain, and stroke. Preclinical data from animal models of these diseases support the potential therapeutic efficacy of inhibiting of AMPA receptors with selective antagonists. Several noncompetitive AMPA receptor antagonists are in clinical trials currently, but none have been approved by for use in humans yet. AMPAR receptor antagonism clearly is viewed as a viable, but not yet validated, therapeutic approach.